Orexin receptor antagonism, a new sleep-enabling paradigm: a proof-of-concept clinical trial

P Hoever, G Dorffner, H Beneš, T Penzel, H Danker-Hopfe, M J Barbanoj, G Pillar, B Saletu, O Polo, D Kunz, J Zeitlhofer, S Berg, M Partinen, C L Bassetti, B Högl, I O Ebrahim, E Holsboer-Trachsler, H Bengtsson, Y Peker, U-M Hemmeter, E Chiossi, G Hajak, J Dingemanse, P Hoever, G Dorffner, H Beneš, T Penzel, H Danker-Hopfe, M J Barbanoj, G Pillar, B Saletu, O Polo, D Kunz, J Zeitlhofer, S Berg, M Partinen, C L Bassetti, B Högl, I O Ebrahim, E Holsboer-Trachsler, H Bengtsson, Y Peker, U-M Hemmeter, E Chiossi, G Hajak, J Dingemanse

Abstract

The orexin system is a key regulator of sleep and wakefulness. In a multicenter, double-blind, randomized, placebo-controlled, two-way crossover study, 161 primary insomnia patients received either the dual orexin receptor antagonist almorexant, at 400, 200, 100, or 50 mg in consecutive stages, or placebo on treatment nights at 1-week intervals. The primary end point was sleep efficiency (SE) measured by polysomnography; secondary end points were objective latency to persistent sleep (LPS), wake after sleep onset (WASO), safety, and tolerability. Dose-dependent almorexant effects were observed on SE , LPS , and WASO . SE improved significantly after almorexant 400 mg vs. placebo (mean treatment effect 14.4%; P < 0.001). LPS (–18 min (P = 0.02)) and WASO (–54 min (P < 0.001)) decreased significantly at 400 mg vs. placebo. Adverse-event incidence was dose-related. Almorexant consistently and dose-dependently improved sleep variables. The orexin system may offer a new treatment approach for primary insomnia.

Trial registration: ClinicalTrials.gov NCT00640848.

Figures

Figure 1
Figure 1
Treatment effects of almorexant on objective sleep variables. Mean changes relative to placebo with 95% CIs. CI, confidence interval.
Figure 2
Figure 2
Treatment effects of almorexant on subjective sleep variables. Mean changes relative to placebo with 95% CIs. CI, confidence interval; SSA, self-rating sleep and awakening quality questionnaire.
Figure 3
Figure 3
Treatment effects of almorexant on next-day alertness and performance (reaction time test). Mean changes relative to placebo with 95% CIs. CI, confidence interval; VAS, visual analog scale.

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